Organophosphorus compound is (OP) are a common class of chemicals used as pesticides, herbicides, and nerve agents The nerve agents soman (3-(Fluoro-methyl-phosphoryl)oxy-2,2-dimethyl-butane), sarin (2-(Fluoro-methylphosphoryl)oxypropane), VX (S-2-[diisopropylamino]O— ethyl methylphosphonothioate), tabun (ethyl N,N-dimethylphosphoramidocyanidate) and Novichok agents are among the most lethal weapons of mass destruction ever developed. Some of these nerve agents were used with catastrophic results in wars and also in terrorist attacks in Japan in the 1990s. The majority of pesticides are also OPs (such as parathion, fenthion, malathion, diazinon, dursban, chlorpyrifos, terbufos, acephate, phorate, methyl parathion, phosmet, azinphos-methyl, and dimethoate), and intoxication with these compounds represents a major public-health concern worldwide. Chlorpyrifos, the organophosphate agent of dursban, is found in some popular household roach and ant sprays, including Raid™ and Black Flag™.
Due to their physical state and high lipophilicity, OPs rapidly penetrate and accumulate in the central nervous system (CNS). OP poisoning of military personnel on the battlefield and of common citizens in the event of a terrorist attack with nerve agents has caused an increase in concern for public and governmental authorities around the world in recent years. In addition, increased demand for food and ornamental crops has resulted in an increase in the use of toxic OP-based pesticides, including parathion and malathion, in developed and developing countries, which has resulted in an increase in the accidental poisoning of farmers and gardeners. The possibility of further terrorist attacks with nerve agents and the escalating use of OP pesticides underscore the urgent need to develop effective and safe antidotes against OP poisoning.
Although different OPs interact with specific targets in the peripheral and central nervous systems, signs and symptoms of acute intoxication with high doses of nerve agents or OP pesticides appear to result in part from their common action as irreversible inhibitors of acetylcholinesterase (AChE), the enzyme that catalyzes the inactivation of the neurotransmitter acetylcholine (Bajgar, J. (2004) Adv. Clin. Chem. 38, 151-216). In the periphery, acetylcholine accumulation leads to persistent muscarinic receptor stimulation that triggers a syndrome whose symptoms include miosis, profuse secretions, bradycardia, bronchoconstriction, hypotension, and diarrhea. OP poisoning also leads to overstimulation followed by desensitization of nicotinic receptors, causing severe skeletal muscle fasciculations and subsequent weakness. Central nervous system-related effects include anxiety, restlessness, confusion, ataxia, tremors, seizures, cardiorespiratory paralysis, and coma.
OPs are also known to cause an Intermediate Syndrome (IMS), which results in muscle weakness in the limbs, neck, and throat that develops in some patients 24-96 hours after poisoning; long-term nerve damage sometimes develops 2-3 weeks after poisoning. Researchers from Sri Lanka, Australia, and the UK recently showed that changes in neuromuscular transmission patterns often occur before a physician can make an IMS diagnosis from clinical signs. About 38% of patients studied presented with muscle weakness that was not severe enough for an IMS diagnosis. Thus, IMS is a spectrum disorder. At one end of the spectrum the patients demonstrate only the electrophysiological abnormalities without clinically detectable muscle weakness, and at the other end, patients progress to severe muscular weakness with deterioration of electrophysiological measurements and the risk of respiratory failure.
None of the current therapies for treating or preventing OP poisoning and IMS have been ideal. Therefore, there is still a critical need for an effective and safe method of treating or preventing OP poisoning. This and other objects and advantages, as well as additional inventive features, will become apparent from the detailed description provided herein.